Dialysis apparatus and process for controlling the phosphate level of blood

ABSTRACT

An apparatus for purifying blood has a blood compartment and a clearance compartment separated by a semi-permeable membrane. The apparatus includes a device containing a cation exchange resin charged with metal ions whose phosphates are insoluble in water. Metal salts of iron, aluminum, zirconium, lanthanum, thorium and tin are deposited on a cation exchange material and the charged cation exchange resin is contacted with dialysis liquid. The process of treating blood with the dialysis liquid is also contemplated.

This is a continuation of application Ser. No. 70,630 filed Aug. 29,1979, now abandoned, which in turn is a division of application Ser. No.895,057, filed Apr. 10, 1978, now U.S. Pat. No. 4,213,859.

The invention relates to an apparatus for the purification of blood,provided with at least one selectively permeable membrane, a bloodcompartment on one side of the membrane and a clearance compartment onthe other side thereof, through which compartments there are passedrespectively the blood and a clearance liquid for removing the wasteproducts from the blood, and a sorbent which is in contact with theclearance liquid and serves to extract phosphates from the liquiddischarged from the clearance compartment.

It is known that hemodialysis may be successfully used especially in thecase of chronic renal insufficiency. The blood of the patient is fedexternally of the body through an artificial kidney in which harmfulwaste products such as urea, creatinine, uric acid, ammonium,phosphates, potassium, and the like are removed. In the artificialkidney the blood to be purified is passed over a selectively permeablemembrane.

This membrane is permeable to water and to the abovementionedlow-molecular waste products, but is not permeable to relatively largeparticles such as red and white blood corpuscles and most plasmaproteins.

The composition of the clearance or dialysis liquid passing through theclearance compartment, i.e. the compartment containing the dialysisliquid, is as a rule adapted to that of normal plasma. As a result, theessential electrolytes will not have such differences in concentrationas would lead to undesired diffusion of these electrolytes to theclearance compartment.

However, it is also known that instead of using a dialysis liquid, theblood may be purified by means of an ultrafilter. The latter also has aselectively permeable membrane, but in the clearance compartment theliquid originating from the plasma contains low-molecular substanceswhich have passed through the membrane because of the application ofpressure on the plasma. After this liquid has been freed from wasteproducts, it is fed back to the blood before the latter is returned tothe patient.

When use is made of a dialysis liquid, it is common practice for it tobe fed to the artificial kidney at a rate of about 500 ml per minute.So, for instance, with a dialysis which lasts 8 hours, 240 liters offresh dialysis liquid are required. The total volume can be prepared inadvance and stored in a big tank (batch-tank system) or it can becontinuously prepared during dialysis by diluting a liquid concentrate(concentrate dilution system). The batch-tank system has thedisadvantage that it calls for the use of a tank having a capacity of ashigh as a few hundred liters, which is difficult to be kept sterile fora long time. The drawback to the concentrate dilution system is that itcalls for an intricate apparatus in order that a proper dilution maycontinuously be ensured.

The amount of dialysis liquid required may be considerably reduced byemploying a system using activated charcoal and ion exchangers for theregeneration or purification of the dialysis liquid after it has passedthrough the artificial kidney and before it is fed back to theartificial kidney. Such a regeneration system is known from, forinstance, the Netherlands Patent Application No. 7,009,608. In thedescribed regeneration, urea is converted into ammonium carbonate bymeans of urease, after which the ammonium ions are attached to azirconium phosphate cation exchanger. The spent dialysis liquid issubsequently passed over hydrated zirconium oxide which absorbsphosphates from it.

Organic waste products such as uric acid and creatinine, are removedfrom the dialysis liquid with the aid of active carbon. Thus, only a fewliters of dialysis liquid will suffice for carrying out a dialysistreatment.

In another well-known artificial kidney described in U.S. Pat. No.3,617,545 the dialysis liquid is purified by electrodialysis. Thedialysis liquid coming from the artificial kidney is demineralized in anelectrodialyser and subsequently passed through a column of urease forconverting urea into ammonium bicarbonate. Next, the dialysis liquidflows to a cation exchanger which retains the ammonium, and thereafterback to the electrodialyser for recovering the ions lost in the initialpassage, and subsequently through a column of active carbon for theremoval of uric acid and creatinine and finally cleared of phosphatesand sulphates by an anion exchanger (Amberlite IRA 400 or PermutitS1)before being passed back to the clearance compartment of theartificial kidney.

There has been no satisfactory method so far for the removal ofphosphates from the dialysis liquid which usually occur in it in theform of HPO₄ ²⁻ and H₂ PO₄ ⁻.

There are several disadvantages to the use of inorganic ion exchangersfor that purpose. Hydrated or non-hydrated aluminium oxide, forinstance, displays a toxic side effect; a satisfactorily reproduciblepreparation of hydrated zirconium oxide is found to give quite someproblems; and the phosphate-retaining capacity of hydrated iron oxiderapidly deteriorates with time.

Organic anion exchangers are incapable of removing phosphatesufficiently because of the high excess of chloride ions over thephosphate ions in the dialysis liquid.

For instance, strongly basic anion exchangers in this medium will takeup as little phosphate (HPO₄ ⁻⁻) as about 10 meq per liter of ionexchanger.

There has now been found a specific sorbent which has a high capacity,rapidly removes phosphate, and has satisfactorily reproducibleproperties.

The apparatus according to the invention is characterized in that thesorbent used is an organic cation exchange material which is chargedwith ions of a metal whose phosphate is poorly soluble in water.

It should be noted that methods for the removal of phosphate fromliquids with the aid of sorbents are in themselves known to be used forthe purification of sea and waste water. For instance the journalOkeanologya, 13 (1973) 2 and the PB report 203 069 (1970) of the U.S.Nat. Tech. Inform. Service contain descriptions of methods for theremoval of phosphates from sea or waste water using strongly acid cationexchangers charged with/-iron(III)-ions. The technique of thepurification of sea water or waste water, however, is totally differentfrom that employed for the purification of blood, in which case alsomedical requirements are to be considered.

In order that the sorbent may be medically permissible and capable of arapid and high take up of phosphate it should be formed preferably by anorganic cation exchanger charged with iron ions. A particularly suitablesorbent is a cation exchanger charged with iron (III) ions. If assorbent instead of a cation exchanger charged with iron (III) ions thereis used a cation exchanger charged with ions of metals whose phosphatesare also insoluble, such as ions of metals selected from the group ofthorium, tin, lanthanum, aluminum and zirconium, then it should ofcourse be ensured that possible toxic effects as a result of the metalions are effectively controlled. By poorly soluble phosphates are to beunderstood here phosphates having a solubility not higher than 10 mg/1in water.

The cationic exchange resin may be charged with metal ions in anysuitable manner. To this end the cation exchanger may be in a suitableform such as the H⁺ form or entirely or partly in a salt form, forinstance the Na⁺ form. Charging is effected in a known manner, forinstance by means of an aqueous solution of a salt of the particularmetal used. The charging temperature may vary between wide limits, forinstance between 0° and 100° C. The charging time is generally in therange of a few minutes to 10 hours.

Use may be made to advantage of a cation exchanger having weakly acidgroups, because they give rise to only a low concentration in theeffluent of the metal ions with which it is charged (metal leakage). Asexamples of suitable weakly acidic groups may be mentioned carboxylicacid groups, phosphonic acid groups and/or amidoxime groups. Inparticular, the cation exchanger may contain aminocarboxylic acid groupsand/or iminodicarboxylic acid groups, for instance those in which thecarboxylic acid group contains 1 to 5 carbon atoms, more particularlyaminoacetic acid groups and/or iminodiacetic acid groups. It isespecially the last-mentioned type which displays a remarkably low metalleakage.

Despite the advantage of a low metal leakage when use is made of cationexchangers having weakly acid groups, the present invention is not atall limited to devices using this type of cation exchanger. From thepoint of view of phosphate-retaining power the cation exchangers thatcontain strongly acid groups are also very suitable. Moreover, thesorbents prepared therefrom will generally take up considerable amountsof potassium in addition to phosphates, which is of interest sincepotassium is as a rule present in too high concentrations in the bloodof kidney patients. Particularly suitable for a combined take up ofphosphate ions and potassium ions are cation exchangers containingsulphonic acid groups.

Organic cation exchangers are known in themselves and may be prepared inany suitable manner. A weakly acid cation exchange resin containingcarboxylic acid groups may be obtained for instance by hydrolysis of acopolymer of a nitrile or a (meth)acrylic ester or by copolymerizationof (meth)acrylic acid.

A weakly acid cation exchanger with phosphonic acid groups may beprepared for instance by phosphorylation of a matrix followed byoxidation or, for instance, by reaction of a haloalkylated matrix withphosphorus trichloride, followed by hydrolysis of the reaction product.

A weakly acid cation exchanger containing aminocarboxylic acid groupsand/or iminodicarboxylic acid groups may for instance be prepared byhaloalkylation of a matrix, followed by reaction with an aminocarboxylicacid or an iminodicarboxylic acid having 1 to 5 carbon atoms percarboxylic acid group or by preference a derivative thereof such as anitrile or an ester, in which latter case the reaction product issubjected to hydrolysis.

This cation exchanger also may be prepared by bringing a halocarboxylicacid having 1 to 5 carbon atoms or a derivative thereof into reactionwith a haloalkylated and subsequently aminated matrix. Amination may becarried out by means of, for instance, ammonia, ethylene diamine orpolyamines, for instance: tetraethylene pentamine.

A cation exchanger having amidoxime groups may for instance be obtainedby bringing a copolymer having nitrile groups into reaction withhydroxylamine.

A strongly acid cation exchanger having sulphonic acid groups can beprepared in a known manner by, for instance, sulphonation of a matrixwith, for instance, sulphuric acid or chlorosulphonic acid or byreaction of a matrix with sulphur chloride followed by oxidation, asdisclosed in British Patent Specification No. 1,270,127. Optionally, thestrongly acid cation exchangers having aromatic nuclei may further betreated with, e.g. oleum.

The chemical composition of the matrix or the basic polymer of thecation exchanger also may vary. However, it preferably consists of apolymer or a polycondensation product of an aromatic compound and/or a(meth)acryl or vinyl compound, for which with advantage use may be madeof a phenol-formaldehyde resin or a copolymer of a vinyl aromaticcompound and/or an acryl or vinyl compound. For the preparation of thephenol-formaldehyde resin not only basic phenol itself, but also otherphenols, for instance cresols or diphenylol propane may be used.

In the preparation of the polymer from a vinylaromatic compound use maybe made of monovinyl aromatic compounds such as styrene, vinyl toluene,vinyl ethyl benzene, vinyl naphthalene or vinyl anisole, or mixtures ofthe afore-mentioned compounds.

It is preferred that use should be made of styrene. Besides (a)monovinylaromatic compound(s) there may be employed one or more acryl compounds,for instance: acrylonitrile or methacrylonitrile, and/or acrylic ormethacrylic esters. In the preparation of weakly acid cation exchangerspreference is given to the use of acryl compounds. The preparation ofthe matrix also may be carried out in the presence during polymerizationof a cross-linking monomer, for instance in an amount not higher than80% by weight, calculated on the total amount of monomers, which step isnot required, however, if the polymer is as yet cross-linked afterpolymerization, for instance in the haloalkylation or by electromagneticradiation or accelerated electrons. As cross-linking monomer there isused a compound having at least two ethylenically unsaturated groups,for instance, 1,3-butadiene, isoprene or vinyl methacrylate, butpreferably di- or polyvinyl aromatic compounds, such as divinyl ethylbenzene, trivinyl benzene and more particularly technical divinylbenzene (60% by weight of divinyl benzene and 40% by weight of ethylstyrene).

The basic polymer may be prepared in any suitable manner, for instanceby suspension polymerization of one or more monomers at a temperaturegenerally in the range of 10° to 160° C. in the presence of a radicalinitiator, for instance benzoyl peroxide, lauroyl peroxide, cumenehydroperoxide and/or azobisisobutyronitrile.

It is preferred that the matrix of the cation exchanger should bemacroporous, since in that case a very high and rapid phosphate sorptionis obtained. To this end the polymerization may be carried out, ifrequired, in the presence of one or more compounds which can precipitateand/or solvate the polymer to be prepared, for instance: hexane,heptane, cyclohexane, amyl alcohol, cyclohexanol, benzene, tolueneand/or chlorobenzene. Alternatively, a linear polymer, such aspolystyrene, may be dissolved in the monomeric compound(s) and beextracted after polymerization.

The use of a strongly acid cation exchanger with a high degree ofcross-linking of the macroporous matrix is of advantage because such asorbent shows a high selectivity to potassium ions as well as high andrapid phosphate take up. By a matrix having a high degree ofcross-linking is to be understood here a matrix containing at least 10%by weight of a cross-linked monomer.

A much preferred embodiment of the apparatus according to the inventionis characterized in that the sorbent is also charged with alkaline earthmetals, more particularly calcium ions and/or magnesium ions. In thisway the sorption of these ions from the dialysis liquid can becontrolled in order that the correct Ca- and Mg levels in the blood maybe maintained without there being any need for external replenishment ofthese alkaline earth metals.

In another embodiment of the apparatus provided by the invention thesorbent is included in capsules having a cationic semi-permeable wall.Such an embodiment may be of advantage in the case where the sorbentmight give off substances that must not enter the blood. It is alsopossible for the sorbent according to the invention to be used in directcontact with the blood, i.e. without engaging a dialysis circuit. Inthat case it is preferred that the sorbent should be included in acapsule whose wall is compatible with the blood; a suitable material forthis purpose is, for instance, cellulose acetate.

The sorbent may be brought into a reservoir, for instance, a cartridgeor a column, after which the phosphate containing liquid is passedthrough the reservoir in the usual manner. In a different embodimentaccording to the invention the sorbent is contained in the clearancecompartment of the artificial kidney.

After the sorbent has taken up sufficient phosphate, it may optionallybe regenerated, for instance with iron (III) chloride in the case of aniron-charged cation exchanger. If in the regeneration also the metal isremoved, then the cation exchanger can be re-charged with this or someother metal.

In the dialysis care should further be taken that the patient does notdevelop acidosis. Prevention thereof may be effected by giving thepatient a dose of bicarbonate ions. General practice is that for theduration of the dialysis an aqueous solution of sodium acetate is addedto the dialysis liquid, advantage being taken of the fact that theacetate ions pass through the usually employed dialysis membranes andare converted into bicarbonate ions in the patient. Administering sodiumacetate, however, calls for a series of operations and the use ofintricate control apparatus. Moreover, it causes an undesirable increasein the sodium ion concentration in the blood.

The invention also provides an apparatus for adding in a simple andreliable manner the desired amount of bicarbonate ions and/or acetateions at the required speed. To this end use is made of a basic anionexchanger which is at least partly charged with bicarbonate ions and/oracetate ions and exchanges these for chloride ions of the dialysisliquid. It is preferred that the ion exchanger should be strongly basic.The amount of dialysis liquid per unit time coming into contact with theanion exchanger is determinative of the rate at which acetate ionsand/or bicarbonate ions are released. The total amount required can beset with the amount of anion exchanger. It should be added that theorganic anion exchanger which is at least partly charged with acetateions and/or bicarbonate ions also may be used in combination withsorbents and/or ion exchangers other than the ones according to theinvention.

The invention further relates to a method of preparing a cationexchanger charged with metal ions. It is characterized in that before orafter the cation exchanger is charged with the metal ions, it is chargedwith from 10% to 100% alkali metal ions. A weakly acid cation exchangerwith carboxyl groups is preferably charged with at least 80%, and it ispreferred that a weakly acid cation exchanger with iminodicarboxylicacid groups should be charged with 40-60% by weight alkali metal ions.

Sodium ions are particularly suitable. An alkali metal charge isparticularly of importance for strongly acid cation exchangers in orderto inhibit metal leakage and/or a decrease in pH value during dialysis.To this end and to increase the phosphate retaining power it is also ofimportance that the pH value during and/or after charging with the metalions is set to an appropriate value.

The invention further relates to a method for the preparation ofsubstances for decreasing the potassium and/or the phosphate level inthe blood. It is characterized in that as sorbent an organic cationexchanger charged with metals selected from the group comprisingthorium, iron, tin, lanthanum, aluminum and zirconium is brought into aform suitable for oral administration.

The invention also comprises the shaped articles suitable for oraladministration made by the process according to the present invention.The sorbent may for instance be contained in capsules at least one ofthe walls of which dissolve in the intestinal canal, so that the sorbentcan take up phosphate there.

It is apparent that in that case the sorbent must not be toxic.Moreover, in the case of oral administration the sorbent may becontained in capsules having a cationic semi-permeable wall. This may beof importance if a direct contact of the solvent with its environmentshould be avoided.

FIG. 1 is a schematic representation of a hemodialyser. An artificialkidney 1 which has two compartments 3 and 4 separated by a selectivelypermeable membrane 2, i.e. a blood compartment 3 and a clearance ordialysis compartment 4. The membrane may be in any desirable form, forinstance in that of flat or tubular film, or it may be a large number ofhollow fibers. The blood compartment 3 is connected to the circulatorysystem of a patient by means of blood tubes 5 and 6. If necessary, theextracorporal transport of the blood may be assisted by a blood pump 7.Dialysis liquid flows through compartment 4 and circulates through adialysis circuit 9 by means of a dialysate pump 8.

In the dialysis circuit 9 there is a regeneration device 10 whichpurifies the dialysis liquid from the waste products it has taken upfrom the blood in compartment 4. The regeneration device may consist ofseveral parts connected in series or in parallel, which each serve toeliminate one or more waste products. One of these parts is a column 11containing the sorbent provided by the invention for the removal ofphosphates from the dialysis liquid. If required, the sorbents may bemixed in a particularly desired ratio and be contained in one column.After the dialysis liquid has passed through the column 11, it goesthrough a column 12 containing active carbon for the removal of uricacid and creatinine from the dialysis liquid. In the active carbon ofcolumn 12 there is placed a tube 13 containing a basic anion exchangerwhich is at least partly charged with a material containing acetate ionsand/or bicarbonate ions.

This tube serves to keep the acetate and the bicarbonate content of thedialysis liquid at the desired level. However, it is also possible forthe active carbon of column 12 to hold two tubes which respectivelycontain acetate charged and bicarbonate charged basic anion exchangers.The tube 13 is so dimensioned and constructed that only a particularpart of the total stream of dialysis liquid flows through it, so that anadjustable release of acetate and bicarbonate may be obtained. It isalso possible for the tube to be placed in a column packed with adifferent material or to be placed in a separate by-pass line throughwhich there flows only part of the dialysis liquid.

PREPARATION OF IMINODIACETIC ACID CATION EXCHANGER

A macroporous copolymer consisting of 86% by weight of styrene and 14%by weight of technical divinyl benzene was chloromethylated indichloroethane with monochloromethyl ether in the presence of aluminiumchloride as catalyst. One part by weight of the product was brought intoreaction with 2 parts by weight of diethyl ester of aminodiacetic aciddissolved in toluene. The resulting product was hydrolysed, after whichthe nitrogen content of the dry cation exchanger obtained was 5% byweight (calculated on dry weight).

PREPARATION OF SORBENTS I--III

From the above-described iminodiacetic acid cation exchanger thefollowing three sorbents were prepared.

I After 300 ml of the cation exchanger had been brought into the acidform by means of 2N H₂ SO₄ it was stirred for one hour in the presenceof 300 ml of an FeCl₃ solution in a concentration of 2 eq/liter, andsubsequently washed with soft water. The charge was then 950 meq Fe(III)/liter cation exchanger.

II After 300 ml of the cationic exchanger had been brought into the 50%Na⁺ form using 2N NaOH, it was stirred for 1 hour in the presence of 300ml of an Fe Cl₃ solution in a concentration of 2 eq/liter. Subsequently,the pH was brought to a value of 5.0 with an aqueous Na HCO₃ solution.Next, the cation exchanger was stirred for one hour and washed with softwater. The charge was then 1670 meq Fe (III)/liter cation exchanger.

III The cation exchanger which had been brought to about 50% of the Na⁺form in accordance with Example II was charged with Fe (III) with onepart by volume of Fe Cl₃ solution (2 eq/liter) and washed with softwater. Subsequently 2 parts by volume of a solution of CaCl₂ (1000meq/liter and Mg Cl₂ (350 meq/liter) were added to it, followed bystirring for one hour, the pH being kept at a value of 5 by means ofsodium bicarbonate. After washing for a short time the Fe (III) chargewas 1650 meq/l cation exchanger.

PREPARATION OF SULPHONIC ACID CATION EXCHANGER

One part by weight of macroporous copolymer of 70% by weight of styreneand 30% by weight of technical divinyl benzene was sulphonated byheating it with 8 parts by weight of 98% H₂ SO₄ for 2 hours at 75° C.and subsequently for 4 hours at 100° C. After slow dilution and washingwith water the product (A) obtained had a capacity of 1850 meq/l.

A part of the macroporous cation exchanger A obtained was aftertreatedby adding over a period of 30 minutes 1 part by weight of sodiumsulphate and 10 parts by weight of oleum containing 65% by weight ofsulphur trioxide per 1 part by weight of the cation exchanger.

The mixture was heated for 4 hours at a temperature of 110° C.Subsequently it was slowly diluted and washed with water. The product(B) obtained had a capacity of 2270 meq/l.

In order to prepare a sulphonic acid cation exchanger by activation withsulphur chloride, followed by oxidation 1 part by weight of themacroporous copolymer described above was left to swell in 2 parts byweight of S₂ Cl₂. The swollen beads were cooled to -15° C., and 2 partsby weight of liquid SO₂ were added. Then, over 1 hour, 2 parts by weightof ClSO₃ H were added, the reaction mixture being maintained at -15° C.by cooling. The temperature of the reaction mixture was next allowed toincrease slowly and finally it was heated for 12 hours at 60° C. Thebeads were washed with carbon disulphide and subjected to a suctionaction until they were air-dry. The polymer sulphide and/or polysulphidethus obtained was first oxidized for 1 hour with 30% by weight nitricacid at a temperature of between 30° and 50° C., and then oxidized byheating for 40 minutes with 60% by weight nitric acid at 90° C. Aftercooling, the product was washed with water. Four parts by volume of acopolymer C containing SO₃ H groups were obtained (per part by weight ofcopolymer starting material) and having a capacity of 2255 meq/l.

PREPARATION OF SORBENTS IV--XI

From the above-described non-aftertreated sulphonic acid cationexchanger A the sorbents IV - IX were prepared.

IV 300 ml of the cation exchanger together with 300 ml of a FeCl₃solution in a concentration of 2 eq/liter were stirred for one hour at25° C., followed by washing with soft water. The charge was then 1600meq Fe (III)/liter cation exchanger.

V Example IV was repeated, with the exception that after the cationexchanger had been brought into contact with the FeCl₃ solution, the pHwas raised to a value of 5.5 by means of an NaHCO₃ solution followed bystirring for one hour. After washing with soft water the charge was 1720meq Fe (III)/liter cation exchanger.

VI After 300 ml of the cation exchanger had been brought into the Na⁺form until acid-free by percolation with an excess of 6% NaCl solution,it was contacted for one hour at 25° C. with 300 ml of an FeCl₃ solutionin a concentration of 2 eq/liter, and washed with soft water. The chargewas then 1650 meq Fe (III)/liter cation exchanger.

VII Example VI was repeated in such a way that subsequent to the washingtreatment 1 part by volume of cation exchanger was after-washed with 3parts by volume of aqueous 1% NaHCO₃ solution and washed with softwater. The charge was then 1645 meq Fe (III)/liter of cation exchanger.

VIII One part by volume of the sorbent obtained according to Example VIwas charged with Ca⁺⁺ and Mg⁺⁺ by stirring the sorbent for 30 minutes inthe presence of one part by volume of a solution of CaCl₂ (1000meq/liter) and MgCl₂ (250 meq/liter). After the sorbent had been washedwith soft water, it was after-washed with one part by volume of anaqueous 0.1% NaHCO₃ solution and again washed with soft water. Thesorbent then took up very little Ca⁺⁺ and Mg⁺⁺ from the dialysis liquid.The iron charge was 850 meq/liter cation exchanger.

IX After 1500 ml of the cation exchanger had been brought into the Na⁺form by percolation with an excess of aqueous 6% NaCl solution, it wasstirred for one hour in the presence of 1500 ml of aqueous FeCl₃solution having a concentration of 200 meq/liter. After the sorbent hadbeen washed with soft water it was charged with Ca⁺⁺ and Mg⁺⁺ withstirring for one hour in the presence of 1500 ml of an aqueous solutionof CaCl₂ (1300 meq/liter) and Mg Cl₂ (140 meq/liter). After it had beenwashed with soft water it was after-washed with 1500 ml of a 0.1% NaHCO₃ aqueous and again washed with soft water. The iron charge was then150 meq/liter cation exchanger.

Sorbent X was prepared according to Example IX, with the exception,however, that use was made of the pre-treated cation exchanger B, in anamount of 1000 ml. The solution of the alkaline earth metal salts had aCaCl₂ concentration of 1200 meq/liter. The sorbent obtained had an ironcharge of 180 meq/liter cation exchanger.

Sorbent XI was prepared according to Example IX, with the exception,however, that use was made of the sulphonic acid cation exchanger C inan amount of 1000 ml. The solution of the alkaline earth metal salts hada MgCl₂ concentration of 160 meq/liter. The sorbent obtained had an ironcharge of 190 meq/liter exchanger.

PREPARATION OF CARBONIC ACID CATION EXCHANGER

A macroporous, carbonic acid cation exchanger was prepared by hydrolysisof a macroporous copolymer of 40% by weight of ethyl acrylate, 44% byweight of acrylonitrile and 16% by weight of technical divinyl benzene.The weakly acid capacity was 2300 meq per liter of cation exchanger.

XII After 300 ml of the cation exchanger had been brought entirely intothe Na⁺ form by means of aqueous 2N NaOH it was contacted for one hourat 25° C. with 300 ml of an aqueous Fe Cl₃ solution having aconcentration of 3 eq/liter. The pH was then brought to a value of 6 bymeans of an aqueous NaOH solution and stirring was continued for onehour. Subsequently, the cation exchanger was washed with soft water. Thecharge was then 2175 meq Fe (III) per liter of cation exchanger.

With the experimental set up illustrated in FIG. 2 the above-describedsorbents were tested in vitro. In FIG. 2 a vessel 15 charged with 34liters of a model aqueous liquid having the starting composition*mentioned in Table 1.

*The starting pH of the two liquids was set to 7.4 by means of somehydrochloric acid. From the start of the experiment 184 meq phosphate(as HPO₄ ²⁻) were fed to the model liquid over a period of 30 minutes;in this way no precipitate was formed in the model liquid.

                  TABLE 1                                                         ______________________________________                                                        Model liquid                                                                             Dialysis liquid                                    ______________________________________                                        Na.sup.+        139.5  meq/l   139.5  meq/l                                   K.sup.+         3.0    meq/l   3.0    meq/l                                   Ca.sup.++       3.5    meq/l   3.5    meq/l                                   Mg.sup.++       1.0    meq/l   1.0    meq/l                                   Cl.sup.-        107.0  meq/l   107.0  meq/l                                   Acetate         15.0   meq/l   25.0   meq/l                                   Bicarbonate     25.0   meq/l   15.0   meq/l                                   Phosphate (as HPO.sub.4.sup.--)                                                               0      meq/l   0      meq/l                                   Urea            1.0    g/l     0      g/l                                     Creatinine      0.1    g/l     0      g/l                                     ______________________________________                                    

In Examples IX-XI the model liquid contained 6.44 meq K⁺ /liter insteadof 3 meq K⁺ /liter. The potassium concentration in the dialysis liquidwas then 0 meq K⁺ /l instead of 3 meq K⁺ /liter.

The model liquid, the components of which occur in correspondingconcentrations in the human blood, circulated through the bloodcompartment 16 of a dialyser 17 at a rate of 200 ml/min. The dialyserhad a semi-permeable membrane of cupramonium cellulose film, known underthe trade name Cuprophan. The membrane had a thickness of 18 μm and asurface area of 1.3m². A dialysis liquid supplied from a 6-liter buffervessel 19 circulated through the clearance compartment 18 at a rate of500 ml/minute. The dialysis liquid was of the composition given inTable 1. After the dialysis liquid had left the clearance compartment18, it passed through a column 20, containing a sorbent according to theinvention. The vessels 15 and 19 were kept at a temperature of 37° C.The phosphate concentration and the acidity of the liquid in the vessel15 were measured as a function of time and the amount of phosphate takenup by the sorbent expressed as milliequivalents was calculated.Moreover, the calcium, magnesium and iron concentrations in the vessel15 were measured. The experiments were carried out with the sorbents Ithrough XII in amounts of 300 ml each, except for the sorbents IX--XI,which were used in amounts of 1100 ml, 750 ml and 750 ml, respectively.In the following Table 2 are listed the phosphate, calcium, magnesiumand iron ions concentrations of the model liquid in the vessel 15measured after 360 minutes. It also gives the lowest pH values observedin the vessel 15 and the total amounts of phosphate taken up by thesorbent, which are also given per liter of sorbent.

The difference in the rate of removal of phosphate in theabove-mentioned experiments were only small.

                                      TABLE 2                                     __________________________________________________________________________    Meq HPO.sub.4.sup.2-                                                                    Meq HPO.sub.4.sup.2-                                                taken up  taken up                                                                             Model liquid                                                 Sor-                                                                             by sor-                                                                              per liter                                                                            Meq   Meq Meq                                                bent                                                                             bent   of sorbent                                                                           HPO.sub.4.sup.2- /1                                                                 Ca.sup.2+ /1                                                                      Mg.sup.2+ /1                                                                       ppm Fe                                                                             pH min.                                  __________________________________________________________________________    I  39     130    3.62  0.7 0.5  <0.1 6.9                                      II 83     276    2.53  0.8 0.6  <0.1 7.2                                      III                                                                              78     261    2.64  3.0 0.9  <0.1 7.2                                      IV 90     299    2.36  1.7 0.9   1.5 6.7                                      V  76     253    2.70  1.8 0.9   0.5 7.4                                      VI 99     329    2.12  1.7 0.9   0.7 7.5                                      VII                                                                              71     236    2.83  1.6 0.9  <0.1 7.4                                      VIII                                                                             83     276    2.53  3.4 1.0  <0.1 7.4                                      IX 99      90    2.13  3.3 1.0  <0.1 7.4                                      X  90     120    2.35  3.5 0.9  <0.1 7.4                                      XI 100    133    2.09  3.3 1.0  <0.1 7.4                                      XII                                                                              69     231    2.87  --  --   <0.1 7.2                                      __________________________________________________________________________

To find out the influence of cation exchangers charged with metal ionsother than Fe⁺⁺⁺ additional experiments were carried out with theabove-described iminodiacetic acid cation exchanger charged with ions ofone of the metals of the group of aluminium, zirconium, lanthanum,thorium and tin.

In each experiment, 50% of the cation exchanger was brought into the Na⁺-form by means of 2N NaOH. This was followed by washing with soft water.Subsequently, the cation exchanger was stirred for 3 hours in thepresence of a solution of a salt of one of the above-mentioned metals ofthe group of aluminium, zirconium, lanthanum, thorium and tin.

In all cases the metal salt solution contained 3300 meq of the metalsalt per liter of the starting cation exchanger. As metal salts wereused AlCl₃.6H₂ O, ZrOCl₂.8H₂ O, LaCl₃.H₂ O, Th(NO₃)₄.4H₂ O and SnCl₄.5H₂O.

The results of the measurements after a dialysis lasting 360 minutes arelisted in the following Table 3.

                  TABLE 3                                                         ______________________________________                                                  Meq HPO.sub.4.sup.2-  Meq HPO.sub.4.sup.2-                                    per liter  Meq HPO.sub.4.sup.2-                                                                     taken up                                                of dialy-  taken up   per liter                                     Metal     sis liquid by sorbent of sorbent                                    ______________________________________                                        Al        2.92       67         224                                           Zr        3.28       53         176                                           La        2.91       68         225                                           Th        2.07       101        337                                           Sn        4.20       16          53                                           ______________________________________                                    

Unless otherwise indicated all "liquids" and solutions used herein arewater or aqueous solutions. Also unless otherwise stated, all parts andpercentages are by weight.

WHAT IS CLAIMED IS:
 1. In a method for the preparation of a cationexchanger charged with metal ions adapted for controlling the phosphatelevel in blood by oral administration, the steps which comprise charginga cation exchanger with from 10% to 100% alkali metal ions before orafter it is charged with ions of iron (III), tin, lanthanum, aluminum orzirconium.
 2. The method of claim 1, wherein the said alkali metal ionsare sodium and the said metal ions which react with phosphate ions areiron III ions.
 3. A phosphate sorbent for oral administration capable ofcontrolling the phosphate level in blood comprising an organic cationexchanger charged with ferric ions in a pharmaceutically acceptablecarrier.
 4. A phosphate sorbent according to claim 3 comprising a weaklyacid organic cation exchanger.
 5. The phosphate sorbent of claim 4wherein the cation exchanger contains carboxylic acid groups, phosphonicacid groups or amidoxime groups.
 6. The phosphate sorbent of claim 5wherein the cation exchanger contains aminocarboxylic acid oriminodicarboxylic acid groups.
 7. The phosphate sorbent of claim 5wherein the cation exchanger contains aminoacetic acid or iminodiaceticacid groups.
 8. The phosphate sorbent of claim 3 wherein the cationexchanger is a strongly acid cation exchanger.
 9. The phosphate sorbentof claim 3 wherein the cation exchanger has a high degree ofcross-linking.
 10. The phosphate sorbent of claim 8 wherein the cationexchanger contains sulphonic acid groups.
 11. The phosphate sorbent ofclaim 3 wherein the cation exchanger has a matrix comprising a polymeror a polycondensation product of an aromatic compound, an acryl, amethacryl or a vinyl compound.
 12. The phosphate sorbent of claim 3wherein the cation exchanger has a macroporous matrix.
 13. The phosphatesorbent of claim 3 wherein the cation exchanger contains alkali metalions.
 14. The phosphate sorbent of claim 13 wherein the alkali metalions are sodium ions.
 15. The phosphate sorbent of claim 13 wherein thecation exchanger contains calcium or magnesium ions and the alkali metalions.
 16. The phosphate sorbent of claim 3 wherein the pharmaceuticallyacceptable carrier is a capsule having a cationic semipermeable wall.